Lack of progress in lowering rates of preterm delivery (PTD) in the U.S. has stimulated investigations into potential explanatory factors that are outside the current realm of prenatal care. These include factors at the micro'level, such as genes, and factors that are 'upstream'such as acute/chronic stress and social class gradient which has consistently been shown to be related to PTD. There are a growing number of studies focusing on immune system-related genes and PTD because of strong evidence that some pathways to PTD have an infection and/or inflammation component. However, most of these studies have lacked information on other relevant biomarkers (e.g.cytokines, bacterial vaginosis), underlying pathologic processes (e.g. chorioamnionitis, placental infarcts, incomplete conversion of spiral arteries), and upstream factors(e.g. maternal stress), making it difficult to contextualize gene polymorphism-PTD findings. The proposed study builds on the NIH funded, multi-ethnic, community-based Pregnancy Outcomes and Community Health (POUCH) Study of women enrolled in mid-pregnancy from 52 clinics in 5 Michigan communities. The POUCH study has data on prenatal maternal social conditions, health behaviors, psychological well-being, medical complications, histopathologic abnormalities of placenta/fetal membranes, vascular-related DNA polymorphisms, and mid-pregnancy biomarkers (e.g. maternal cortisol, plasma CRH, serum and vaginal fluid cytokines). In this CDC-funded "add on" to the POUCH study we have expanded our research team to include preeminent researchers in the area of PTD-related gene polymorphisms. We have selected nine immune system-related gene polymorphisms (TLR-4, CD14, MBL. IL-lra, TNFR2, MMP-9, Fas, TNFa and IL-1/3) that will be evaluated in 1,363 POUCH case-cohort mothers (311 preterm;1,052 term), and 818 case-cohort offspring. Gene polymorphisms, as main effects and as modifiers of other relevant risk factors (e.g. bacterial vaginosis, stress), will be assessed in relation to PTD overall and PTD-subtypes (e.g., <35 weeks'gestation, spontaneous labor intact membranes, PROM, histopathologic evidence of chorioamnionitis). This study of gene polymorphisms, situated within the rich database of the POUCH study, offers : 1) a chance to learn more about underlying processes leading to PTD that may involve maternal and/or fetal gene polymorphisms and gene-environment interactions: and 2) a chance to determine if maternal gene polymorphisms are useful, along with other biomarkers, as predictive factors that could guide selective enrollment into clinical trials with interventions targeted at specific underlying processes.